John william blag-den



Patented July 9, 1929.

UNITED STATES PATENT OFFICE.

JOHN WILLIAM BLAGDEN, OF LONDON, ENGLAND, ASSIGNOR OF ONE-HAL]? T HOT/V- .ARDS & SONS LIMITED, OF ILFORD, ENGLAND.

MANUFACTURE OF HYDROGENATEI) .ALKALOIDS.

No Drawing. Application filed March 20, 1926, Serial No. 96,319, and in Great Britain March 24, 1925.

In presence of a colloidal metal of the platinum group and in acid solution, the cinchona alkaloids can be hydrogenated at t0--5 U, by hydrogen to produce heXahydro-derivativos, but so far as has been known hitherto, in the presence of a nickel or nickel suboxide catalyst, the hydrogenation does not proceed beyond the dihydro-derii'vatives. Hence the more costly platinum catalyst has appeared to be necessary for producing the higher hytire-derivatives.

By the present invention a cinchona alkaloid, such as quinine or cinchonidine, or a substitution derivative thereof, can be hydrogen ated to form the hexahydroderivative by the action of hydrogen in presence oi a nickel catalyst or another catalyst of the nickel group (which includes nickel, iron, cobalt and copper) at a raised temperature. Be-

sides the economy of working as compared with the known process, there is the advantage that is not necessary to operate in an acid solution. The additional hydrogenation is not appreciable at temperatures below 30 (l. but above this temperature, and preferably at (BO -80 0., the absorption oil? hydrogen occurs readily and continues until the hexahydroderivative has been formed.

In British specifications Nos. 21,883 of 1914 and 21,9 oi. 1914 the hydrogenations of quinine to hydro-quinine in aqueous or al.- coholic solution in presence of nickel suboxide, is described and it is stated that the hydrogcnation can occur at ordinary temperature and pressure or slightly raised pressure and that the temperature and pressure can be varied within Wide limits. In the examples, however, the temperature used is about 30 C. and the product obtained is dihydroquinine. In fact, at the date of the said specilications liexahydroquinine was not known, and its production by the process 01 the said specifications cannot occur at ordinary temperature.

As parent material. for the invention the nonhydrogenated alkaloid or substitution product may be used, in which case the hydrogenation may be conducted at a raised temperature from the first, or it may be conducted first at ordinary temperature and then at a raised temperature.

Alternatively, the parent material may be the dihydro-derivative of the alkaloid or substitution product, the hydrogenation being conducted at! a raisedtemperature lrom the first.

The parent nuiterial may be used in the form of a base e r a salt and may be dissolved in water, alcohol or other suitable SOlVGllt.

The following examples illustrate the invention, the parts being by weight Example 1.5 parts of quinine base are dissolved in 100 parts of absolute alcohol and the solution is agitated at 20 C. with 3 to at parts of a nickel catalyst in an atmosphere of hydrogen under pressure of 20 to l0 lbs. per square inch. The gas is readily absorbed until the quantity representing the production of dihydro-quinine has been taken up, when it ceases. The temperature is now raised to above 40 C. whereupon gas absorption sets in again at a slower rate than be tore; the temperature is raised slowly until double the amount of gas has been absorbed as was absorbed in the first stage, by which time the final temperature may be about 80 C. The hexahydroquinine produced isolated solution.

Example .2.5 parts of quinine base are dissolved in 150 parts oi. alcohol 0f 30 per cent strength and the solution is treated with catalysts and hydrogen as is described in Example 1.

Imam/2712c Er parts of quinine hydrochloride are dissolved in 150 parts of water and the solution is agitated in a hydrogen atmosphere at a pressure of about 1-0 lbs. per square inch with 3 or 4 parts of a nickel catalyst. The initial temperature of C. is raised gradually to about 7 5 C. When absorption of hydrogen has ceased the hexahydroquinine base is isolated from the solu tion in known manner.

Emmnplc 4.- parts of dihydroquinine baseare dissolvedinl20 parts of adsolute alco- 1101 and the solution is agitated with 8 to 10 parts of a nickel catalyst at a temperature of C. in an atmosphere of hydrogen under a pressure of about 40 lbs. per square inch, After absorption has ceased the solution is .liltered and the hexahydroquinine obtained by evaporation of the solvent.

Ewalmple 5.10 parts of cinchonidine hydrochloride are dissolved in 150 parts of Water and the solution is agitated with l to 5 part-sot a nickel catalyst in a hydrogen at mosphere under a pressure of about 4.0 lbs.

b eva ioratin the lilter d per square inch. The hydrogen corresponding with the production of the dihydro-body is absorbed at a temperature of C. When this absorption has ceased the temperature is raised above C. and. a fresh gas absorption occurs and continues until the hexahydro-cinchonidine is formed, the final ten'iperature of the catalyst being about C. The new base is isolated from the aqueous solution in known manner.

The nickel 'atalyst used in the foregoing examples may be prepared by reducing commercial nickel carbonate in hydrogen at a low-temperature, which may conveniently be 260 C.

Having thus fully described the nature of the said invention and the best means I know of carrying the same'into practical etlect, I

claim v 1. A process for the manufacture ot hydrogenated cinchona alkaloids, which process consists 1n sub ecting material selected from the group consisting of the cinchona alkaloids, their dihydro derivatives, and salts of the said alkaloids and dihydro derivatives in presence of a solvent for the material and of a catalyst ot' the nickel group to the action of hydrogen at a temperature which at least in the later stagesot the reaction is not less than 40 C.

' hydro-derivative of the alkaloid.

3. A process for the manufacture of hexahy'droquinine, whlch process consists in sub jecting material selected from the group consisting of quinine, dihydro-(piinine and salts oli both these bodies in presence o l a solvent for the material and a catalyst ol' the nickel group to the action of hydrogen at a temperature which at least in the later stages ol the reaction is not less than l0 G.

4. A process for the manufacture of hexahydroquinine, which process consists in causing material selected from the group consisting of quinine, dihydro piinine and salts of both these bodies to absorb hydrogen in presence of a catalyst of the nickel group at a temperature above 30 C. until the quantity of hydrogen absorbed correspomls with the formation of hexahydroquininc.

5. A process tor the manufacture ol' hydrogenated cinchona alkaloids, which process consists in causing material selected lirom the group consisting of the cinchona alkaloids, their dihydro derivatives, and salts ol" the said alkaloids and dihydro derivatives to absorb hydrogen in presence of-a catalyst of the nickel group at a temperature above 30 C. until the quantity of hydrogen absorbed corresponds with the conversion of at least a substantial portion of the parent material into a he ;ahydro-deriwitive of the alkaloid.

6. A process for the manufacture of hexahydroquinine, which process consists in causing material selected from the group consisting of quinine, dihydroquinine and salts of both of these bodies to absorb hydrogen in presence of a catalyst of the nickel group at a temperature above 30 C. until the quan tity of hydrogen absorbed corresponds with the conversion of at least a substantial portion of the parent material into hexahydroquinine.

In testimony whereof I have signed my name to this specification.

JOHN lVILLIAM BLAGDEN. 

